New bis-alkylammonium ethers



NEW BIS-ALKYLAMMONIUM ETHERS Jorgen Fakstorp, Copenhagen, Denmark,assignor to Aktiebolaget Pharmacia, Uppsala, Sweden, a corporation ofSweden No Drawing. Application March 17,1953, Serial No. 342,963

I Claims priority, application Denmark March 25, 1952 3 Claims. (Cl.260-501) This invention relates to the Water-soluble, non-toxic salts ofa new alkyl ammonium ether which can be represented by the generalformula:

wherein X represents the non toxic anion of the salt, which may be theacid tartrate or the bromide, for example.

Said new compounds according to the invention have provide to possess agood biological activity,'especially as highly potent and usefulganglionic blocking agents. Thus, these ethers have been tested (in theform of their salts) as ganglionic blocking agents and have been foundto be very active with respect to their ability to block thetransmission across the ganglia of both the sympathic and parasympathicnervous systems.

The prior art discloses bis-alkylammonium hexanes and pentanes asganglionic blocking agents. However, for example, thetriethylammoniumethyl-dimethylethylammoniumethyl ether bis-monohydrogentartrate, a preferred compound according to the invention, is active inblocking the transmission across the superior cervical ganglion of thecat, as shown by its ability to prevent the nictitating membranecontraction evoked by electrical stimulation of the said ganglion, evenin a concentration less than two thirds of that required byhexamethonium bromide, a commonly used agent of said prior known type.

The free hydroxides of the compounds according to the invention arerather unstable crystalline or glasslike solids, which are very solublein water and in polar organic solvents. They form salts readily with twoequivalents of an acid. These salts are readily soluble in water andless readily soluble in polar organic solvents, they are sparinglysoluble in non-polar organic solvents. Among the acids which may be usedto form salts of these organic quaternary ammonium hydroxides areinorganic acids such as hydrochloric, hydrobromic, hydroiodic, sulfuric,phosphoric, and strong organic acids such as aikylsulfuric,arylsulfonic, citric, tartaric, lactic, fumaric, maleic and similaracids which in therapeutic dosages provide nontoxic anions.

The salts according to the invention may be prepared, for example, bythe interaction of sodium dimethylaminoethoxide with diethylaminoethylchloride followed by quaternization of the resulting2-dimethylaminoethyl-2'- diethylaminoethyl ether with a reactiveethylating agent, such as diethylsulfate or ethyl bromide.

The hydroxides may be set free from their salts by means of appropriatereagents, such as silver oxide, barium hydroxide, or by hydrolysis withsulfuric acid followed by a treatment with barium hydroxide. From thefree hydroxides the salts may be prepared by interaction of theequivalent amounts of the appropriate acids, suitably in aqueoussolution.

A preferred manner of carrying out the invention in 2 practise is byheating together in a non-polar solvent of sufiiciently high boilingpoint, e. g. toluene, sodium alkoxides, prepared by interaction of theappropriate aminoalcohol by direct reaction with sodium, with sodiumhydride, or with finely powdered sodium hydroxide, with chlorides,prepared from the hydrochloride of the approsaponification with aqueousI priate aminoalkyl chloride by alkali, extraction with toluene anddrying of the toluene extract, immediately prior to use, and isolatingthe bistertiary alkyl amine either by distillation or by p re'cipitatingit as a salt e. g. the hydrochloride.

It has been found convenient to heat or to keep a room temperaturedepending on the boiling point of the reagents, when reacting theappropriate bis-tertiary ether, together with an appropriate alkylbromide, alkyl iodide,

alkyl sulfate or alkyl sulfonate, in a solvent, preferably acetone,benzene, toluene and ethyl ether, or mixtures of these and containingvarying amounts of alcohol to facilitate the alkylation reaction.

In carrying out the inventionthe following aminoalcohols may suitably beused: dimethylaminoethanol and diethylarninoethanol.

Suitable aminoalkyl halides are especially: dimethylaminoethylchlorideor the corresponding bromide.

Further, use may preferably be made of the, following reactivealkylating agents: methyl iodide, ethyl bromide, dimethylsulfate anddiethylsulfate'.-

The following examples illustrate in more detail my invention without,however, limiting it in scope or spirit.

Example 1 An alkoxide is prepared from 117 g. of diethylaminoethanoldissolved in 500 ml. of toluene, by addition of 23 g. of sodium, whileheating the mixture under reflux. When the sodium has dissolved, asolution of 108 g. of dimethylaminoethylchloride in 500 ml. of tolueneis added at once, and the mixture is heated under reflux for thefollowing 4.hours. Sodium chloride, formed in the reaction, is removedby filtration. The toluene is removed by evaporation and the residue isdistilled under reduced pressure.Z-diethylaminoethyl-Z'-dimethylaminoethylether distills at 103 C. at 15mm. pressure. Analysis of a sample of the base showed 64.1% carbon,12.7% hydrogen and 14.9% nitrogen: the calculated values are 63.8%carbon, 12.8% hydrogen and 14.9% nitrogen. 94 g. of the compound isdissolved in a mixture of 70 ml. of acetone and 30 ml. of anhydrousethanol, to which solution is added under stirring and external cooling170 g. of methyl iodide dissolved in 250 ml. of acetone. A vigorousreaction ensues and 110 g. of the bis-methoiodide ofZ-dimethylaminoethyl-2'-diethylaminoethylether is precipitated as awhite crystalline mass, which is removed on a filter and dried Example 2In an atmosphere of dry nitrogen a solution of 89 g. ofdimethylaminoethanol dissolved in 300 ml. of dry toluene is addeddropwise to a stirred boiling suspension of 24 g. of sodium hydride inml. of dry toluene. After all the sodium hydride has reacted, a solutionof diethyl- Patented Apr. 24, 1956 After removal of salt and tQluene, asdescribed in Ex- W h -f i m n l fi h l l 5 wherein X- represents anon-toxic anion forming a wateretherqis distilled at reduced.;.pressure;as.dessetibedtin.Ex-

ample .1.

9.0-.g..0f.the aboveproductis. mixed with. 106g. diethy lsulfate whilestirring and .coo1ing .external1y-. After the first Mz has been added.avigorous reaction startsand emixm erbecomesselid. Th nrodue is hen r mv from the reaction vessel andfdispersed in. ether, filteredand,crystallized from acetone. The bisvethosulfate has.

the...melting point of 80-? C.., andanalysis of. agsample.

showed 5.63% nitrogen; the calculatedamount is. 5.64%,- it o en- 118 g.oithis .bisrethosulfate. is dissolvedin 500ml. of,

25%. sulfuricacidand boiledwith-refluxtor several-.hQui-s.

The illfurieacid-is nentralizedwith.theequivalentamoum.

fjbariurn. hydrOX de, dissqlved. in. 2 liters .of hot. water, the,barium. sulfateremoyed. by filtration. and. thereac: tion mixtureevapfiratedto a final volurneof. 7.00? 1111.

To 400ml. of the above. solution isadded ZADLmLIpf;

a 1 N solutionof tartaric. acid. Thewater is.e.vagora ted in vacuumandtl e, residual; oiLtriturated with. dry. acetqnes until itcrystallizes; the acid bis-tartrate cryfitallizestwith amele ate h h isrcmov dby lke pingnthewsalt over concentrated. sulfuric acid in vacuum:This tartrate.

has the melting point 182,? C.

What I claim is;

1. The non-toxic salts of a new alkyl ammoniumether:

having the general formula:

References;sited iUithQlfilQ'Qf this. patent FOREIGN PATENTS Belgium -aMay'3=l-, 1952 OTHER REFERENCE-s Levis et al.: Arch. Intern.Pharmacodynarnie, vol. 93 (195-3.), PP-.

.Morrisonet 9.1.: Arch. Intern..Pharmacodynamie," vol. 86 1951 pp.203-12..

Paley: Comp tes Rendus Soc. Biol., vol. (1946),

Marxer' et" al.: pp. 924-31.

Ewinsz Biochemicallounfi. 3.6667 (1914).

Helv. Chim. Acta," vol. 34' (i951),

Kahane et .al..: Bull. Soc. Chem. (France) 6, 647.'48.

KunkeLetaL: Fed. Proced. 11, 365.-('March'1952).

1. THE NON-TOXIC SALTS OF A NEW ALKYL AMMONIUM ETHER HAVING THE GENERALFORMULA:
 2. THE NEW COMPOUND2-DIMETHYLETHYLAMMONIUMETHYL-2''-TRIETHYLAMMONIUMETHYL ETHERBIS-MONOHYDROGENTARTRATE.